Hypertension Management: A Moving Target

9:45 :30am Hypertension Management: A Moving Target SPEAKER Karol Watson, MD, PhD, FACC Presenter Disclosure Information The following relationships exist related to this presentation: Karol E. Watson, MD, PhD, FACC, serves on the Clinical Trials Adjudication Committee for Merck & Company and is a consultant for Daiichi Sankyo. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Hypertension Management: A Moving Target Learning Objectives Review the JNC8 guidelines for hypertension in adults, with special attention to new blood pressure goals 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8) Consider patient factors such as age, comorbidities, and race when prescribing antihypertensive therapy JAMA. Published online December 18, 2013. doi:.01/jama.2013.284427 Important to Note RCTs conducted 1966 to present Minimum 1-year follow-up period Sample size > 0 JNC 7 was The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure JNC 8 is the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults In JNC 8 they give 9 Evidence based Recommendations these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient. Grade A B Strength of Recommendation Strong recommendation: There is high certainty based on evidence that the net benefit is substantial. Moderate recommendation: There is moderate to high certainty based on evidence that the net benefit is moderate to substantial C Weak recommendation: There is at least moderate certainty based on evidence that there is a small net benefit. 1 D Recommendation against: There is at least moderate certainty based on evidence that it has no net benefit or that risks/harms outweigh benefits. 0 Expert opinion ( There is insufficient evidence or evidence is unclear or conflicting, but this is what the Panel recommends. ) 5 E Net benefit is unclear. Balance of benefits and harms cannot be determined because of no evidence, insufficient evidence, unclear evidence, or conflicting evidence, but the Panel thought it was important to provide clinical guidance and make a recommendation. Further research is recommended in this area. No recommendation for or against ( There is insufficient evidence or evidence is unclear or conflicting. ) Net benefit is unclear. Balance of benefits and harms 0 N cannot be determined because of no evidence, insufficient evidence, unclear evidence, or conflicting evidence, and the Panel thought no recommendation should be made. Further research is recommended in this area. 2 3

Recommendation #1 1. In patients aged 60 years, initiate pharmacologic treatment in systolic BP 150mmHg or diastolic BP 90mmHg and treat to a goal systolic BP <150mmHg and goal diastolic BP <90mmHg. (Strong Recommendation Grade A) In other words: Ease up on Hypertension Treatment in Older Adults (60 years of age or older) Treat if BP >150/90 Aim for <150/90 HYVET Trial: Study Design Prospective. Randomized. Double Blind. Placebo-Controlled. Mean follow-up 1.8yrs 3845 patients > 80 years with HTN and systolic blood pressure 160 mm Hg Inclusion Criteria: Exclusion Criteria: Aged 80 or more, Standing SBP < 140mmHg Systolic BP; 160-199mmHg Stroke in last 6 months + diastolic BP; <1 mmhg, Dementia; Need for daily nursing care R Active Treatment Placebo 1.5 mg Indapamide SR (± Matching Dose perindopril) n=1912 n=1933 Target blood pressure 150/80 mmhg Primary Endpoint: fatal and non-fatal strokes Secondary Endpoints: death from: stroke, cardiovascular causes, cardiac causes and any cause N Engl J Med 2008;358/ACC 2008 Hypertension in the Elderly Two treat-to-target trials in the elderly Japanese Trial to Assess Optimal SBP (JATOS) 4416 patients aged 65-85 (average age of 74) Randomized to SBP<140 vs. SBP 140-160 Achieved BP of 136/75 vs. 146/78 No difference in CV events or renal failure (p=0.99) VALISH trial 3079 patients aged 70-84 (average age of 76) Randomized to SBP<140 or SBP 140-149 No significant reductions in stroke, CV events, or renal failure JATOS Study Group. Hypertens Res 2008;31:2115-27. Ogihara T et al. Hypertension 20;56:196-202. Antihypertensive Use Linked to Serious Fall Risk in Elderly Patients 4961 hypertension patients enrolled in Medicare interviewed about total number of antihypertensive medications and average total daily dose Followed for 3 years, using claims data to track fall injuries 446 (9%) experienced serious fall injuries, and 837 (16.9%) died during follow up. In multivariate analysis, patients who used antihypertensive medications had increased risk of serious falls compared with nonusers hazard ratio 1.4 for high intensity antihypertensive therapy hazard ratio 1.28 for moderate intensity antihypertensive therapy Among the 503 participants who had previously sustained an injury after a fall, the hazard ratios was 2.31 JAMA Intern Med. 2014;174(4):588-595. SBP (mm Hg) Postural Changes in Blood Pressure are more common as we Age 190 170 150 130 1 ELDERLY YOUNG 90 7 8 9 11 12 1 Time (hours) www.gerontologyindia.com/ppt/presentation-htn-elderly.ppt

Recommendations #2 and #3 2. In patients aged <60 years, initiate pharmacologic treatment at DIASTOLIC BP 90mmHg and treat to a goal <90mmHg. For ages 30 59 years, Strong Recommendation Grade A For ages 18 29 years, Expert Opinion Grade E 3. In patients aged <60 years, initiate pharmacologic treatment at SYSTOLIC BP 140mmHg and treat to a goal <140mmHg. Expert Opinion Grade E For Adults under 60 years of age Treat if BP >140/90; Aim for <140/90 There s strong evidence for treating high diastolic BP in patients 30-59 years of age. Everything else is Expert Opinion What???? You mean treating SBP > 140 mm Hg is only Expert Opinion? Prior guidelines relied on epidemiologic evidence and observational studies that noted that the risks for cardiovascular events in untreated adults increased rapidly as SBP increased above 140 mm Hg Older trials actually used a DBP goal rather than a SBP goal The older trials that did use a SBP goal, targeted < 160 So, direct RCT evidence to support this threshold is limited. JNC 8 acknowledges this limitation Recommendations # 4 & 5 5. 4. In patients aged 18 years with chronic diabetes kidney mellitus disease, initiate pharmacologic treatment at systolic BP 140mmHg or diastolic BP 90mmHg and treat to goal systolic BP <140mmHg and goal diastolic BP <90mmHg. (Expert Opinion Grade E) Earlier HTN guidelines lowered treatment goals for adults with CKD and DM; but JNC 8 gives the same BP goals in these patients as in the general population. BP goal <140/90 Hypertension in CKD Modification of Diet in Renal Disease (MDRD) Randomized to a MAP < 93 (120/80) vs MAP < 7 (140/90) RESULT: No CV or renal benefit African American Study of Kidney Disease randomized to a MAP < 93 vs MAP 2-7; Achieved BP 130/78 vs 141/86 RESULT: No CV or renal benefit Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L et. al. N Engl J Med 330:887 884, 1994 Wright JT Jr et. al. Arch Intern Med. 2002;162:1636-1643. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial NHLBI,251 Type 2 diabetics Three Trial arms Glycemic control BP Lipids BP arm 4,773 randomized to SBP<120 or <140 ACCORD Trial: Blood Pressures Mean # Meds Intensive: 3.2 3.4 3.5 3.4 Standard: 1.9 2.1 2.2 2.3 Average after 1 st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2 The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 20 Mar 14 The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 20 Mar 14

Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD Death HR = 0.88 95% CI (0.73-1.06) ACCORD Trial: Outcomes HR = 0.59 95% CI (0.39-0.89) NNT for 5 years = 89 Total Stroke The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 20 Mar 14 ACCORD Trial: Adverse Events Intensive N (%) Standard N (%) P Serious AE 77 (3.3) 30 (1.3) <0.0001 Hypotension 17 (0.7) 1 (0.04) <0.0001 Syncope 12 (0.5) 5 (0.2) 0. Bradycardia or Arrhythmia 12 (0.5) 3 (0.1) 0.02 Hyperkalemia 9 (0.4) 1 (0.04) 0.01 Renal Failure 5 (0.2) 1 (0.04) 0.12 egfr ever <30 ml/min/1.73m 2 99 (4.2) 52 (2.2) <0.001 Any Dialysis or ESRD 59 (2.5) 58 (2.4) 0.93 Dizziness on Standing 217 (44) 188 (40) 0.36 The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 20 Mar 14 Recommendations #6 6. In the general nonblack population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic, CCB, ACE inhibitor, or ARB. (Moderate Recommendation Grade B) This recommendation is different from the JNC 7 in which the panel recommended thiazide-type diuretics as initial therapy for most patients. While JNC 7 recommended thiazide-type diuretics as the initial antihypertensive choice for all, JNC 8 broadens the choices to also include CCB, ACE-I, and ARBs along with thiazide-type diuretics. NOTE: ßblockers are OUT 28 ALLHAT Chlorthalidone 12.5-25 mg Hypertension Trial 42,418 high-risk hypertensive patients STEP 1 AGENTS (Double-blind) Amlodipine 2.5- mg 90% previously treated % untreated Lisinopril -40 mg Doxazosin 1-8 mg N=15,255 N=9,048 N=9,054 N=9,061 Step 1 agents titrated and atenolol, clonidine, reserpine, and/or hydralazine added as needed to achieve BP goal JAMA 2002; 288: 2981-2997 ALLHAT.2.16 Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group RR (95% CI) p value A/C 0.98 (0.90-1.07) 0.65 L/C 0.99 (0.91-1.08) 0.81 Cumulative CHD Event Rate.12.08.04 Chlorthalidone Amlodipine Lisinopril..β blockers should not remain first choice in the treatment of primary hypertension... The Lancet 2005; 366:1545-1553 0 0 1 2 3 4 5 6 7 Years to CHD Event JAMA 2002; 288: 2981-2997

Comparison of Diuretics and Blockers and Their Effects on CV Events Outcome Relative Risk (95% CI) Psaty BM, et al. JAMA. 2003;289:2534-2544. P Value CHD 0.87 (0.74-1.03) 0. CHF 0.83 (0.68-1.01) 0.07 Stroke 0.90 (0.76-1.06) 0.20 CVD Events 0.89 (0.80-0.98) 0.02 CVD Mortality 0.93 (0.81-1.07) 0.34 Total Mortality 0.99 (0.91-1.07) 0.73 0.4 Favors Diuretics Favors -Blockers 0.6 0.8 1.0 1.2 1.4 Relative Risk Recommendations #7 7. In the general black population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic or CCB. For general black population Moderate Recommendation - Grade B For black patients with diabetes: Weak Recommendation Grade C) JNC 8 recommends a thiazide-type diuretic or CCB as the initial choice in African Americans, but there s less certainty about African Americans with diabetes due to lack of data (they were torn about not including ACE/ARB) ALLHAT Black subjects Chlorthalidone BP Results by Treatment Group in Black Participants Black subjects Amlodipine Black subjects Lisinopril ALLHAT Blacks Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Interval Nonfatal MI + CHD Death 1. (0.94-1.28) All-Cause Mortality 1.06 (0.95-1.18) Combined CHD 1.15 (1.02-1.30) Combined CVD 1.19 (1.09-1.30) Stroke 1.40 (1.17-1.68) Heart Failure 1.30 (1. - 1.54) End Stage Renal Disease 1.29 (0.94-1.75) Wright JT, Dunn JK, Cutler JA et al. JAMA 2005:293:1595-1608. 0.50 1 2 Favors Lisinopril Favors Chlorthalidone Wright JT, Dunn JK, Cutler JA et al. JAMA 2005:293:1595-1608. Recommendation # 8 8. In the population aged 18 years with chronic kidney disease, initial (or add-on) antihypertensive treatment should include an ACE inhibitor or ARB to improve kidney outcomes. (Moderate Recommendation Grade B) In adult patients with CKD, make sure an ACE-I or an ARB is part of the antihypertensive regimen ACE-I or ARB in CKD reduces progression of kidney disease Study Pts Design RR for kidney disease progression Maschio et al 1996 583 Benazapril v. placebo 53% Gisen group 1997 166 Ramapril v. placebo 48% Hou et al 2006 224 Benazapril v placebo 43% Brenner et al 2001 1513 Losartan v. placebo 22%

Recommendation # 9 Thiazide-type diuretic, CCB, ACE-I or ARB 9. If goal BP is not reached within a month of treatment, increase the dose of the initial drug or add a second drug from one of the classes in Recommendation 6. If goal BP cannot be reached with two drugs, add and titrate a third drug from the list provided. Do not use an ACEI and an ARB together in the same patient. If goal BP cannot be reached using only the drugs in Recommendation 6 antihypertensive drugs from other classes can be used. (Expert Opinion Grade E) Don t dilly dally. If BP is not at goal within a month, use one of these 3 strategies : 1. Increase the dose of the initial drug 2. Add a 2nd, then a 3rd drug (Rec #6) (Not an ACE + ARB together) 3. Add a drug from other classes ONTARGET Telmisartan vs. Telmisartan + Ramipril: Primary Outcome (MI, Stroke, CV death, CV hospitalization) Cumulative Hazard Rates 0.0 0.05 0. 0.15 0.20 0.25 Ramipril + Telmisartan Telmisartan Follow-up (yrs) 0 1 2 3 4 The ONTARGET Investigators N ENGL J MED 2008; 358:1547-1559April, 2008 ONTARGET Adverse Events with Ramipril + Telmisartan Ram N=8576 Ram + Tel N=8502 RR P Hypotension 149 406 2.75 <0.0001 Syncope 15 29 1.95 0.032 Cough 360 392 1. 0.1885 Diarrhea 12 39 3.28 0.0001 Angioedema 25 18 0.73 0.30 Renal 60 94 1.58 0.0050 Impairment Any Discontinuation 2099 2495 1.20 <0.0001 JNC 8 in a nutshell Ease up on hypertension treatment in older adults (Adults over 60 years goal < 150/80) In all others blood pressure goal < 140/90 Including those with diabetes and CKD Initial antihypertensive therapy can be a thiazide-type diuretic, CCB, ACE inhibitor, or ARB In black patients initial therapy should be with a CCB or ACE inhibitor In adults with CKD, make sure an ACE-I or an ARB is part of the antihypertensive regimen Don t dilly dally The ONTARGET Investigators N ENGL J MED 2008; 358:1547-1559April, 2008 JNC 8 Algorithm Adult (age > 18 years) Lifestyle Interventions to be applied throughout Treatment Algorithm Set Blood Pressure Goal and Initiate Blood Pressure Lowering Medications Age > 60 years Blood Pressure Goal SBP <150 mm Hg DBP <90 mm Hg Age < 60 years NON-BLACK Initiate Thiazide-type diuretic, or ACEI or ARB or CCB alone or in combination Blood Pressure Goal SBP <140 mm Hg DBP <90 mm Hg All ages with DM Blood Pressure Goal SBP <140 mm Hg DBP <90 mm Hg BLACK Initiate Thiazide-type diuretic, or CCB alone or in combination All ages with CKD Blood Pressure Goal SBP <140 mm Hg DBP <90 mm Hg ALL RACES Initiate ACEI or ARB alone or in combination with other drug classes Select a drug titration strategy A. Maximize first drug B. Add second drug before reaching max of first C. Start with 2 meds If goal BP not reached A. Reinforce Adherence B. Add or titrate drugs above C. Add drugs from other classes CLINICAL PEARL # 1 Two main physiologic systems control blood pressure

Renin-Angiotensin-Aldosterone Regulation of Blood Pressure Renin Substrate Renin Aldosterone The role of aldosterone is to retain sodium in the face of chronic deficiency Angiotensin I Adrenal Cortex Angiotensin II Vasoconstriction CNS Sympathetic Nervous System Regulation of Blood Pressure Cardiac Output Adrenergic Tone Afterload Catecholamines Arteries Resistance Renin secretion Angiotensin Aldosterone Adrenal Gland Sodium & Water Reabsorption Blood Pressure http://vasoactivetherapy.com/files/corlopam.ppt Blood Pressure http://vasoactivetherapy.com/files/corlopam.ppt CLINICAL PEARL # 2 There is a characteristic circadian rhythm to blood pressure CLINICAL PEARL # 3 There is a characteristic life-cycle pattern to blood pressure Blood Pressure Distribution in the Population According to Age 150 130 1 80 70 Men Women 150 130 PP 1 PP 80 70 30-39 40-49 50-59 60-69 70-79 80 30-39 40-49 50-59 60-69 70-79 80 Age PP=Pulse Pressure. Age CLINICAL PEARL # 4 Failure to use enough medication is a common cause of resistant hypertension Adapted from : Third National Health and Nutrition. Examination Survey, Hypertension 1995;25:305-13

Rule of TENS for SBP mmhg Baseline Monotherapy -20-30 A B A 1 Additional Drug for Every Additional mmhg Reduction in Blood Pressure C B A Diuretics and BP Control In states of sodium (and water) excess, diuretics are essential Most classes of antihypertensive agents lead to sodium retention, as compensation for lower BP JNC 8 recommends a thiazide-type diuretic, as one of four initial antihypertensive choices in the general population JNC 8 recommends a thiazide-type diuretic, as one of twp initial antihypertensive choices in the Black patients Cushman W and Basile J. of Clinical Hypertension Thiazide Diuretics Differ in Their Antihypertensive Effects CLINICAL PEARL # 5 In many patients with HTN, adequate diuresis is ESSENTIAL for BP control Change in Ambulatory Systolic Blood Pressure (mm Hg) Week 8 Week 0 6 2-2 -6 - -14-18 -22-26 -30 Office Blood Pressure* Week 2 Week 4 Week 6 Week 8 4.5 ± 2.1 7.6 ± 2.8 9.3 ± 3.2.8 ± 3.5 15.7 ± 2.2 17.4 ± 2.9 19.6 ± 3.4 17.1 ± 3.7 p = 0.001 p = 0.069 p = 0.9 p = 0.842 Hydrochlorothiazide 50 mg daily Chlorthalidone 25 mg daily Hours 6am 8am am 12pm 2pm 4pm 6pm 8pm pm 12am 2am 4am Ernst ME, et al. Hypertension. 2006;47:352-358, Hypertension 2014 Hypertension is common and will likely affect most individuals at some point in their lifetime CLINICAL PEARL # 6 In patients with Resistant Hypertension switching the diuretic from HCTZ to Chlorthalidone may improve BP control (but watch electrolytes!) Guidelines on how best to treat hypertension are evolving and sometimes contradictory For information on prevention, detection and evaluation of hypertension, JNC 7 and international guidelines offer guidance Inadequate treatment is also a common cause of resistant HTN (rule of s) Potassium sufficiency is critical to BP control